Processes for producing doxorubicin, daunomycinone, and derivatives of doxorubicin

ABSTRACT

Daunomycinone is a known precursor of the well known antibiotic and antineoplastic, doxorubicin. Daunomycinone may be synthesized by preparing mono ketal of a 1,4-naphthoquinone as the precursor of the CD rings of daunomycinone followed by preparing a precursor for ring A with C 6  and C 11  attached and the stereochemistry at C 7  and C 9  established and coupling it to CD and then completing ring B.

RELATED CASES

This application is a continuation-in-part application of United Statesapplication Ser. No. 07/542,902 filed Jun. 22, 1990, in the name ofDesmond M. S. Wheeler for Processes for Producing Doxorubicin, now U.S.Pat. No. 5,200,513. Daunomycinone, and Derivatives of Doxorubicin.

BACKGROUND OF THE INVENTION

This invention relates to a process for producing doxorubicin(adriamycin), and derivatives of doxorubicin, through a novel synthesisof daunomycinone and its derivaties. These mycinones can be coupled byknown methods to daunosamine to produce doxorubicin and itscorresponding derivatives.

It is known that doxorubicin is isolated from Streptomyces peucetius. Asuitable process for this isolation is described by F. Arcamone, in"Duxorubicin Anticancer Antibiotics," (Academic Press, New York (1981).Moreover, synthetic routes to doxorubicin are known and these aresummarized, for example, by F. Arcamone (loc. cit.), K. Krohn, Angew.Chem. Int. Ed. Engl., volume 25 (1986), page 790 and Tetrahedron, volume46 (1989), page 291 and T. R. Kelly, Tetrahedron Symposium-in-Print,volume 40 (1984), pages 4537-4793.

A representative prior art procedure for converting daunomycinone toadriamycin is that proposed by Arcamone et al., U.S. Pat. No. 3,803,124.The prior art methods of obtaining daunomycinone have the disadvantageof being expensive.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a novel synthesis ofdoxorubicin.

It is a still further object of the invention to provide a novel processfor synthesis of derivatives of doxorubicin.

It is a still further object of the invention to provide a novel processfor the synthesis of doxorubicin and its derivatives in which the A ringis made stereo selectively with its functionality already establishedand then joined to the CD portion, with the relationship between the C-7and C-9 hydroxyls established stereoselectively before the tetracyclicskeleton is constructed.

It is a still further object of the invention to provide a novel processfor the synthesis of daunomycinone that proceeds in DCAB order with theB ring formed last.

It is a still further object of the invention to provide a novel processof producing intermediates for the synthesis of daunomycinone, namely,methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylateand the 3,5-acetonide of methyl3alpha,5alpha-dihydroxy-5beta-(tri-methylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate.

It is a still further object of the invention to provide novel syntheticroutes to daunomycinone and derivatives of this compound.

In accordance with the invention a novel synthesis of daunomycinone isprovided in which the A-ring precursor of the compound is synthesizedfrom m-anisic acid. The A-ring precursor, methylcis-2,3-epoxy-5-hydroxy-5-(trimethylsilylethynyl)-cyclohexane-1-carboxylate,is converted to methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylatewhich is nitromethylated to produce the required 2alpha-nitromethylcompound. The 3,5-acetonide of the 2alpha-nitromethyl compound iscoupled with a 4-mono ketal of a juglone alkyl ether and cyclized to atetracyclic intermediate. The latter can be converted to daunomycinoneand many of its derivatives.

More specifically, this process for the production of daunomycinone,comprises the steps of: (1) condensing methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alphanitromethylcyclohexane-1beta-carboxylateacetonide with 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene in thepresence of 1,8-diazabicyclo[5.4.0]-undec-7-ene in an aprotic solvent toproduce a3-[(2beta-carbomethoxy-4beta-ethynyl-4alpha,6alpha-(di-O-isopropylidene)-cyclohexanyl-1-yl]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene;(2) cyclizing the thus-produced 1-oxotetrahydronaphthalene to produce7alpha,9alpha-(di-O-isopropylidenyl)-7beta-ethynyl-12-hydroxy-6-nitro-4,5,5-trimethoxy-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenone;(3) converting the decahydro-11-naphthacenone to4,5-dimethoxy-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone;(4) oxidizing the thus produced octahydro-11-naphthacenone to7alpha-9alpha-(di-O-isolpropylidenyl)-9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5-12-naphthacenedione;(5) hydrolysing the tetrahydro-5,12-naphthacenedione to6-desoxy-6-nitro-daunomycinone; (6) reducing the nitro compound to6-desoxy-6-aminodaunomycinone; (7) diazotising the amino compound andobtaining from it by standard reactions, daunomycinone, the6-desoxy-6-halo and cyanodaunomycinones and compounds derived from them.

To produce the methyl3alpha,5alpha-dihydroxy-2alpha-nitromethyl-5beta-(trimethylsilylethynyl)-cyclohexane-1betacarboxylate, methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)-cyclohex-1-ene-1-carboxylateis reacted with nitromethane in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene or sodium hydride as well as ahydrogen bond acceptor, e.g. dimethylsulfoxide ortrimethylamine-N-oxide.

To synthesize methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylate,m-anisic acid is subjected to the Birch reduction with lithium inammonia to produce 5-oxocyclohex-2-ene-1-carboxylic acid, followed bymethylation of thus-produced cyclohex-2-ene-1-carboxylic acid to methyl5-oxocyclohex-2-ene-1-carboxylate with diazomethane,trimethylsilyl-ethynylation of thus-producedcyclohex-2-ene-1-carboxylate with cerium dichloridetrimethylsilylacetylene to produce methylcis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate,conversion to an epoxide and opening of the resulting epoxide ring toproduce the cis-3,5-dihydroxy compound.

In this process for synthesizing daunomycinone there are severalespecially significant procedural steps that increase yield greatly,such as: (1) the reaction mixture is kept between -20 to 20 degreescentigrade during esterification with diazomethane; (2) any ethanol andwater present in the esterification reaction mixture is removed byazeotropic distillation with benezene to produce methyl ester; (3)methyl ester is immediately treated with cerium dichloridetrimethylsilylacetylene at a low temperature, such as -50 to -78 degreescentigrade, to prevent formation of a lactone; (4) the epoxide is formedby oxidation with tert.-butylhydroperoxide in the presence of molybdenumhexacarbonyl catalyst and 4A molecular sieves and the epoxide that isproduced is isolated; and (5) the thus-formed epoxide ring is openedwith 1,8-diazabicyclo[5.4.0]-undec-7-ene or sodium methoxide inmethanol. The cerium reagent should be added to the keto ester to avoida migration of the double bond.

A feature of the synthesis is the production of the 4,4-dimethylacetalof 5-alkoxy-1,4-naphthoquinones by oxidation of 5-alkoxy-1-naphthol withiodobenzene diacetate in methanol. The preparation of the5-alkoxy-1-naphthol, in which the alkoxy is of 1-6 carbon atoms, isdescribed in Moore, H. W.; Lee, S.; Rutolo, D.; Sheldon, R., J. Org.Chem., 1978, 43, 2304-2306. Generally, this process may include thesteps of: (1) alkylating 1,5-dihydroxynaphthalene with an excess ofalkyl iodide in the presence of a base, e.g. potassium carbonate in anaprotic solvent to produce 1,5-dialkoxynaphthalene; (2) dealkylating thethus-produced 1,5-dialkoxynaphthalene with an alkali metalalkanethiolate to remove selectively one alkyl moiety; and (3)acidifying the alkoxide that is produced to form 5-alkoxy-1-naphthol.

As can be understood from the above description, the processes of thisinvention permit the manufacture of doxorubicin less expensively andpermit the effective preparation of derivatives thereof.

DETAILED DESCRIPTION

In the synthesis of daunomycinone, a precursor for rings CD and aprecursor for ring A are first synthesized. The precursor for ring A isattached to the precursor for rings CD and ring B is completed afterring A is coupled to rings CD.

More specifically, the precursor for ring A is prepared with C₆ and C₁₁attached and the stereochemistry at C₇ and C₉ established before it iscoupled to CD and ring B is completed after the precursor for ring A iscoupled to CD. The precursor for the A ring with C₆ and C₁₁ attached andthe stereochemistry at C₇ and C₉ established, has the general structureshown in formula 1, wherein W is an ester or similar group capable ofacting as an electron pair acceptor in a Claisen condensation andrelated reactions; X is an umpolung equivalent of an acetyl group suchas acetylide, trimethylsilylacetylide, ethyl or methyl vinyl ether,2-methyl-1,3-dithiane or corresponding dithioacetal or dithioacetaloxide, or cynaohydrin silyl ether or related compounds; Y is 2H, or ifneeded, a suitable protecting group for a 1,3 diol, such as a cyclicketal e.g. acetonide or a cyclic ##STR1## ester e.g. boronate orcarbonate; and Z is a one carbon umpolung of carbonyl such asnitromethyl.

In the preferred embodiment, the precursor for ring A is prepared bymethylation of 5-oxocyclohex-2-enecarboxylic acid to methyl5-oxocyclohex-2-enecarboxylate at a reaction temperature of between -20to 20 degrees centigrade, trimethylsilylethynylation of saidcyclohexenecarboxylate at a temperature of between -50 to -78 degreescentigrade after removal of water and ethanol to produce methylcis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-carboxylate,epoxidation to methylcis-(2,3-epoxy-5-hydroxy)-5-(trimethylsilylethynyl)cyclohexane-1-carboxylateand opening of the resulting epoxide ring to give methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene carboxylate.This example of the synthesis of the intermediate, required forelaboration of the A-ring,3alpha,5alpha-dihydroxy-2alpha-nitromethyl-5beta-(trimethylsilylethynyl)cyclohexane-1beta-carboxylateacetonide is shown in charts 1 and 2. It has been found that anapproximate 70 percent overall yield of methyl ##STR2##cis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylatefrom m-anisic acid can be obtained by keeping the reaction mixture coldduring esterification with diazomethane and removing any ethanol andwater present in the esterification reaction mixture by azeotropicdistillation with benzene; quickly reacting to the thus-produced methylester with added cerium dichloride trimethylsilylacetylide at a lowtemperature to prevent formation of a lactone; forming the epoxide byoxidation with cumene hydroperoxide and titanium tetraisoperoxide atroom temperature or preferably with tert.-butyl hydroperoxide inrefluxing benzene solution in the presence of molybdenum hexacarbonylcatalyst and 4A molecular sieves and isolating the thus-produced epoxideand opening the thus-formed epoxide ring with1,8-diazabicyclo-[5.4.0]-undec-7-ene or preferably by sodium methoxidein methanol. Without the recited precautions and using completelyanhydrous cerium dichloride, the yield from m-anisic acid is less than10 percent.

Methyl3alpha,5alpha-dihydroxy-2alpha-nitromethyl-5beta-(trimethylsilylethynyl)-cyclohexane-1beta-carboxylatewas obtained from methylcis-2,3-epoxy-5-hydroxy-5-(trimethylsilylethynyl)cyclohexane-1-carboxylateor methylcis-3,5-dihydroxy-5-(trimethylsclyethynyl)cyclohexen-1-ene-1-carboxylateby reaction with nitromethane in the presence of1,8-diazabicyclo-[5.4.0]-undec-7-ene and a hydrogen bond acceptor.Alternatively and better, methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2-alphanitromethylcyclohexane-1beta-carboxylate was obtained from methylcis-3,5-dihydroxy-5-cyclohex-1-ene-1-carboxylate-and nitromethane in thepresence of hydrogen bond acceptor and sodium hydride or1,8-diazabicyclo[5.4.0.]-undec-7-ene.

The hydrogen bond acceptor used for the nitromethylation reaction may beselected from the following: hexamethylphosphoramide, dimethyl sulfoxideand NN'-dimethyl-NN'propylene urea or other hydrogen bond acceptors suchas trimethylamine-N-oxide or corresponding phosphorous or arseniccompounds. The preferred acceptor is dimethyl sulfoxide, the morepreferred acceptor is trimethyl amine-N-oxide. Nitromethane also adds tothe 3,5-di-(terbutyldimethylsilyl) ether of the diol. Thenitromethylation is conveniently carried out at ambient temperature fora time necessary to complete the reaction. The required time is of theorder of 2 to 24 hours. If the reaction becomes exothermic, cooling to15 to 25 degrees centigrade is preferred.

An acetonide is formed from3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylateby treatment with an acetonide-forming reagent. Representativeacetonide-forming agents include, but are not limited to,2-methoxypropene. Preferably, the acetonide-forming reagent is2-methoxypropene.

The acetonide-forming reaction is carried out in the presence of acatalyst, such as pyridinium tosylate or p-toluenesulfonic acid. Apreferred catalyst is pyridinium tosylate.

An inert solvent is used for the reaction. Benzene, heptane, toluene arerepresentative of solvents suitable for the reaction. When benzene isused as the solvent, the reaction goes to completion within a fewminutes' heating under reflux. Conditions appropriate for other solventscan be determined by routine experimentation.

The precursor of the CD rings is generally a mono ketal of a1,4-naphthoquinone such as shown in structural formula 2, wherein R isone of OCH₃ or OH or H, and the R₁ groups are dialkyl or --CH₂ --CH₂ --,R₂, R₃, and R₄ are H or R₂ and R₃ are both alkyl or halo and R₁ and R₄are both H or R₁ and R₄ are both alkyl or halo and R₂ and R₃ are H.

Preferably the naphthoquinone is the mono ketal in which R and R₁ areCH₃ and R₂, R₃ and R₄ are H. In the preferred embodiment, the synthesisof a representative 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene isshown in chart 3. The initial steps of the synthesis include alkylationof both hydroxyl groups of 1,5-dihydroxynaphthalene, followed byselective removal of only one alkyl to give 5-alkoxy-1-naphthol. Thealkyl moiety can be selected from primary alkyls of 1-6 carbon atoms,such as methyl, ethyl and n-propyl. The alkyl iodide is used in anamount in excess of that, required to alkylate both hydroxyl groups.Preferably, a molar ratio in the range of 4:1 to 2.5:1 of alkyl iodideto 1,5-dihydroxynaphthalene, is used. Most preferably, the ratio isabout 3.5:1.

The etherification reaction is conducted in the presence of a base,which is normally selected from organic and inorganic bases.Representative bases include, but are not limited to, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine,triethylamine. A preferred base is potassium carbonate. The amount ofbase ##STR3## employed should be in the range of 3.5 moles to 4.5 moles,per mole of 1,5-dihydroxynaphthalene.

The aprotic solvent can be selected from acetone, methylethyl ketone,methylisobutyl ketone, tetrahydrofuran, acetonitrile, dimethylsulfoxide. Preferably, the solvent is acetone.

The alkali metal alkanethiolate, used for removing one alkyl group fromthe intermediate dialkoxy compound can be selected from sodium andpotassium alkanethiolates, having 1-6 carbon atoms in the alkane moiety.Preferably, the alkali metal alkanethiolate is sodium methanethiolate orethanethiolate. The resulting alkali metal alkoxide can be acidifiedwith any mineral acid, of which sulfuric acid, hydrochloric acid andphosphoric acid are representative.

The 5-alkoxy-1-napthol produced in this way can be converted, forexample, to a corresponding juglone alkyl ether 4-ethylene ketal byreaction with ethylene glycol and thallium trinitrate oriodobenzediacetate in methanol and trimethyl orthoformate. A preferredketal for downstream synthesis is1,4-dihydro-4,4-ethylenedioxy-5-methoxy-1-oxonaphthalene, produced from5-methoxy-1-naphthol and ethylene glycol under the conditions stated.

A most preferred product for downstream synthesis is1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene. This is preferablyproduced from 5-methoxy-1-naphthol by reaction with iodobenzenediacetate in methanol with sodium bicarbonate. It will be understoodthat alkanols of 2-3 carbon atoms can be used to produce higher ketalsby a similar process.

The synthesis of daunomycinone and 6-desoxy-6-nitrodaunomycinone frommethyl3alpha,5alpha-dihydroxy-2alpha-nitromethyl-5beta-(trimethylsilylethynyl)cyclohexane-1beta-carboxylateacetonide and a representative1,4-dihydro-4,4-5-trimethoxy-1-oxonaphthalene is shown in chart 4.Condensation to the 1-oxotetrahydronaphthalene is carried out in anaprotic solvent. The aprotic solvent may be selected from dimethylsulfoxide, hexamethylphosphoramide and acetonitrile. Acetonitrile ispreferred. The reaction is carried out at ambient temperature.Conversion to a representative intermediate,3-[(2beta-carbomethoxy-4beta-ethynyl-4alpha,6alpha-(di-O-isopropylidenyl)cyclohexanyl-1-yl]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthaleneis complete within 4-6 days.

The thus-produced 1-oxotetrahydronaphthalene is preferably cyclized withan alkali metal alkoxide of 1-6 carbon atoms. Suitable alkoxides can beprepared from alkanols of 1-6 carbon atoms, as above, and an alkalimetal hydride. Alkali metal hydrides include sodium hydride or potassiumhydride, of which sodium hydride is preferred. Most preferably, thealkali metal alkoxide is sodium methoxide. The cyclization is carriedout in an inert solvent, such as benzene, hexane or toluene.

A representative cyclic product of this condensation is7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-6-nitro-4,4,-5-trimethoxy-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenone(chart 4).

The thus produced decahydro-11-naphthacenone loses methanol in thepresence of an acidic catalyst to yield7alpha,9alpha-(di-O-isopropylidenyl)-4,5-dimethoxy-9beta-ethynyl-12-hydroxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone (chart 5). Possible catalystsinclude sulfonic acids e.g. ##STR4## methanesulfonic acid; pyridiniump-toluenesulfonate is preferred. A variety of aprotic solvents e.g.aromatic hydrocarbons, tetrahydrofuran, methylene chloride may be used;methylene chloride is preferred.

In one embodiment, the thus produced octahydro-11-naphthacenone was thenoxidized to7alpha,9alpha(di-O-isopropylidenyl)9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedione.Oxidizing agents include cerium ammonium nitrate (CAN) and thalliumtrinitrate (TTN); solvents include methanol, acetone and acetonitrile.The preferred conditions are CAN in acetone withdichlorodicyanobenzoquinone (DDQ) added in catalytic amount. The thusproduced 5,12-naphthacenedione is then hydrolysed with acid in thepresence of mercuric oxide to give 6-desoxy-6-nitrodauomycinone (chart5, example 16).

Additionally, the 6-nitro-5,12-naphthacenedione (chart 5) was convertedinto6-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedioneby reduction with SnCl₂ H₂ O in methanol in the presence of sodiumacetate at room temperature and the leuco product reoxidized with ceriumammonium nitrate. The amino compound, which can be hydrolyzed to theamino daunomycine, has been converted into its diazonium compound withamyl nitrite in dimethoxyethane and then acid and finally mercuric oxidewere added to form daunomycinone (example 18). The diazonium compoundcan be also converted by standard reactions to 6-desoxy and6-desoxy-6-halo or cyano daunomycinones. These mycinones can be coupledby known methods to daunosamine to produce daunorubicin and subsequentlydoxorubicin and their corresponding derivatives shown generally instructural formula 3, wherein R is rings C and D of daunorubicin ordoxorubicin or one of their derivatives R₁ is one of COCH₂ OH or COCH₃and X is NO₂, NH₂, Hal, CN or H.

In this embodiment, the aprotic solvent for condensing the acetonidewith 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene is acetonitrile; thethus-produced 1-oxotetrahydronaphthalene is cyclized with sodium hydridein the presence of a catalytic quantity of methanol in toluene; thethus-produced decahydro-11-naphthacenone is converted to theoctahydro-11-naphthacenone in an acidic medium; the thus-producedoctahydro-11-naphthacenone is oxidized to thetetrahydro-5,12-naphthacenedione with the thus-producedtetrahydro-5,12-naphthacenedione being converted to6-desoxy-6-nitrodaunomycinone by hydrolysis and hydration and intodaunomycinone and 6 to 8 daunomycinones in which the substituent at C₆has been changed.

In a further embodiment (chart 6), the aprotic solvent for condensingthe acetonide with 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene isacetonitrile; the thus-produced 1-oxotetrahydronaphthalene is cyclizedwith sodium methoxide; the thus-produced decahydro-11-naphthacenone isconverted to9beta-acetyl-4,5-dimethoxy-6-nitro-7alpha,9alpha,12-trihydroxy-6,6a,7,8,9,10,10a,11-octahydro-11-napthacenoneby hydrolysis with acid in the presence of mercuric oxide in an acidicmedium; the thus-produced 9-beta-acetylocatahydro-11-naphthacenone isoxidized to7alpha,9-alpha-dihydroxy-4-methoxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-5,11,12-naphthacenetrionewith thallium nitrate and the producedoctahydro-5,11,12-naphthacenetrione is converted to daunomycinone.

In another embodiment, shown in chart 7, instead of oxidizing theoctahydro-11-naphthacenone to7alpha,9alpha-(di-O-isopropylidenyl)9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro-7,8,9,10-##STR5## tetrahydro-5,12-naphthacenedione, thenitrooctahydro-11-naphthacenone was treated with ammonia and 25 mL ofmethanol for 24 hours to yield4,5-dimethoxy-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-11-imino-6-nitro-6,6a,7,8,9,10,10a,11-octahydronaphthacene,which was oxidized with cerium ammonium nitrate in wet THF solution withsodium bicarbonate and a catalytic amount of dichlorodicyanobenzoquinoneto yield11-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedioneneedles in 89 percent yield. Preferably, the same product was obtainedin 90 percent yield by refluxing the nitroiminonaphthacene in O₂ /DMFovernight. Chromatography was not needed.

To obtain 11-amino, 6,11-didesoxy-6-nitrodaunomycinone (as shown inchart 8), the nitroaminonaphthacenedione in THF was hydrolysed withsulfuric acid and mercuric oxide.

Alternatively (chart 7), the nitroaminotetrahydronaphthacenedione wasreduced with stannous chloride in methanol with sodium acetate toproduce6,11-diamino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethyl-4-methoxy-7,8,9,10-##STR6## tetrahydro-5,12-naphthacenedione which was then hydrolyzed withacid in the presence of mecuric oxide to6,11-diamino-6,11-didesoxydaunomycinone (chart 7). These daunomycinonesare the first derivatives with two non oxygen groups in ring B.

The amino group in the nitroaminodaunomycinone can be converted by theway of the 11-diazonium salt and standard reactions into halo, cyano andother derivatives (e.g. amides) obtainable from these compouds, thusproducing a series of 6-nitrodaunomycinones substituted at C₁₁. Forexample, chart 9 shows the preparation of11-fluoro-6,11-didesoxy-6-nitrodaunomycinone of example 24.

The 6-nitro group in these compounds can then be reduced to 6-amino andusing standard reactions by way of the 6-diazonium compound, intohydroxyl, desoxy, halo or cyano thus giving further daunomycinonessubstituted at both C₆ and C₁₁ with different groups. The 6,11-diaminocompound can be converted by way of the diazonium compound into 6,11-disubstituted derivatives (halogen, cyano and functionalities derivedfrom these groups) in which the substitutents at C₆ and C₁₁ are thesame. Thus, the work makes available a large number of6,11-daunomycinones which can be coupled with daunosamine ##STR7## toproduce a new series of doxorubicins. Such 6,11-daunomycinones anddoxorubicins may take the form shown as formula 4, wherein R₁ is one of:CH₃ or CH₂ OH; R₂ is one of daunosamine, or H; R₃ is one of --OH, NO₂,NH₂, F, Cl, Br, I, CN and H and groups derived from these; R₄ is one ofOH, NO₂, NH₂, F, Cl, Br, I, CN and H or groups derived or substitutedfor these; and R₅ is OCH₃, OH, or H, R₆ is H, R₇ is H and R₈ is H. Inaddition, ring D could have the following substitution: R₅ and R₆ are H,R₇ and R₈ are alkyl or halo; or R₅ and R₆ are alkyl or halo; and R₇ andR₈ are H.

In this specification, "easily derived 6-analogues and 11-analogues"means analogues in which groups R₃ and R₄ in structural formula 4 aregroups arrived at by known substitution methods for the nitro group atthe 6 position or amino groups at the 6 position or 11 position, similarto those disclosed above. For example, the transformation of R₃ from NO₂to OH, F, Cl, Br, I and CN is effected by reducing NO₂ to NH₂ and thenconverting NH₂ to its diazonium salt with nitrite. The diazonium groupis then converted to OH by boiling the ##STR8## solution and to F bytreatment with HPF₆ followed by 3HF (C₂ H₃)₃ N with ultrasound. Theother derivatives (R₃ =Cl, Br, I and CN) are made by treatment of thediazonium salt with CuX (X=Cl, Br, I and CN).

The transformation of R₄ from NH₂ to OH, F, Cl, Br, I and CN proceedsby: (1) converting NH₂ into the diazonium group; (2) boiling thesolution to give OH; (3) treatment with HPF₆ and then 3HF (C₂ H₃)₃ Nwith ultrasound to provide F at the R₄ position. Addition of CuX whereX=Cl, Br, I and CN provides R₄ =Cl, Br, I and CN. Modifications in R₄precedes those in R₃ except when making R₃ the same as R₄.

By analogy, the compounds in the disubstituted amines are expected toshow anticancer activity. They will also be examined for cardiotoxicity.

EXAMPLES

Without further elaboration it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the following examples, the temperatures are set forth uncorrected indegrees centigrade. Unless otherwise indicated, all parts andpercentages are by weight.

Materials and Methods

¹ H NMR spectra were recorded on a Varian EM-390 (90 MHx), a VarianVXR-200 (200MHx) or a Nicolet 1180 WB (360 MHz) spectrometer. Data arereported as chemical shifts in parts per million referenced totrimethylsilane internal standard (0 ppm) or to the residual chloroformpeak of deuteriochloroform (7.26 ppm). Multiplicity, number of protonsand coupling constants are reported. Couplings and/or coupling constantswere determined using the COSY technique or by proton irradiationexperiments.

¹³ C NMR spectra were obtained on a Varian VXR-200 (50.4 MHz)spectrometer. Chemical shifts are referenced to the center peak of theresidual chloroform triplet (77.0 ppm).

Ultraviolet spectra were obtained on a Hewlett-Packard 8450 UV-Visspectrophotometer.

Infrared absorption spectra were recorded on a Perkin-Elmer Model 283 oran Analect RFX-30 spectrophotometer and are referenced to polystyrene(160 cm⁻¹).

Elemental analyses were carried out by Desert Analytics (Tuscon, Ariz.).

Mass spectra were provided by the Midwest Center for Mass Spectrometry,University of Nebraska-Lincoln.

Melting points were determined in open-end capillary tubes on a Mel-Tempapparatus.

Column chromatography was carried out on E. Merck silica gel 60 (Flash,40-230 mesh) and all thin layer chromatography (TLC) was carried out oncommercial silica gel plates (Analtech Silica HLF 250 m or Merck Silicagel 60F 254).

High performance liquid chromatography (HPLC) was performed on a WatersAssociates Model 600E chromatography apparatus, equipped with a WatersAssociates Model R₄₀₃ Differential Refractometer, using normal-phasesilica gel columns.

Solvents were distilled before use over an appropriate drying agentunder a nitrogen atmosphere. All reactions requiring anhydrousconditions were done under nitrogen in flame-dryed flasks. Solvents wereevaporated using a Buchi rotary evaporator, then by evacuation at about0.10 mm Hg at room temperature.

EXAMPLE 1 5-Oxocyclohex-2-ene-1-carboxylic Acid

The procedure of Biffin et al., Aust. J. Chem., vol. 25 (1972), page1329, was used.

To a stirred slurry of 30 g (0.21 mol) of m-anisic acid(3-methoxybenzoic acid) in 300 mL of liquid ammonia were slowly addedsmall pieces of lithium (3.5 g, 0.5 mol). Additional lithium (0.5 g,0.07 mol) was added to maintain the blue color of the solution. Themixture was stirred for 2 hours and then cautiously quenched with solidammonium chloride (45 g, 0.84 mol).

Ammonia was allowed to evaporate at room temperature. The last traces ofammonia were removed by warming the mixture under aspirator pressure.The resulting residue was dissolved in 200 mL of ice water and acidifiedto pH 1 with conc HCl. The resulting solution was extracted with four100-mL portions of ethyl acetate. The combined ethyl acetate extractswere washed with one 50-mL portion of saturated sodium chloridesolution, dried over sodium sulfate and evaporated to dryness. Crudesemi-crystalline acid (24.1 g) was washed with a small amount of coldether to yield 5-oxocyclohex-2-ene-1-carboxylic acid, off-whitecrystals, mp 98-101 degrees centigrade, lit (Biffin et al., supra, 98 to99 degrees centigrade) yield 80 to 90 percent.

¹ H NMR (CDCl₃): delta values 10.0 (s, 1H, COOH), 5.9 (m, 2H, HC═CH),3.5 (m, 1H, CHCOO), 2.8 (m, 2H, C═CCH₂), 2.5 (m, 2H, CH₂).

EXAMPLE 2 Methyl 5-Oxocyclohex-2-ene-1-carboxylate

A solution of 0.7M diazomethane in ether was slowly added to a solutionof 6.0 g (42.8 mmol) of 5-oxocyclohex-2-ene-1-carboxylic acid in 100 mLof ether at 0 degrees centigrade, with swirling. The addition ofdiazomethane was continued until the bubbling ceased and a yellow colorpersisted. The solution was treated with a rapid stream of nitrogenuntil the yellow color was discharged. The solvent was removed byevaporation. Benzene (100 mL) was added and evaporated at roomtemperature using an aspirator. The residue was placed on a vacuum linefor 2 hours to produce 6.5 g (42.4 mmol, 99 percent) of methyl5-oxocyclohex-2-ene-1-carboxylate (oil).

¹ N NMR (CDCl₃): delta values 5.9 (m, 2H, HC═CH), 3.7 (s, 3H, COOMe),3.5 (m, 1H, HCOO), 2.9 (m, 2H, C═CCH₂), 2.7 (m, 2H, CH₂).

EXAMPLE 3 Methylcis-5-Hydroxy-5-(trimethylsilylethynyl)-cyclohex-2-ene-1-carboxylate

A solution of n-butyllithium (2.5M, 16.8 mL, 42.1 mmol) was addeddropwise, via a syringe, to a stirred solution oftrimethylsilylacetylene (7 mL, 46.8 mmol) in 120 mL of tetrahydrofuran(THF) at -78 degrees centigrade. The resulting slurry was stirred at -78degrees centigrade for 15 minutes and transferred via a cannula toslurry of 13.45 g (54.6 mmol) of cerium trichloride in 80 mL of THF at-78 degrees centigrade. The cerium chloride had been obtained by dryingcerium trichloride heptahydrate (20.4 g, 54.6 mmol) at 140 to 160degrees centigrade/0.1 mm Hg for 2 hours. Nitrogen was admitted to thecooled flask and 80 mL of dry THF was added to the resulting slurry,which was stirred overnight under nitrogen.

After the addition was complete (45 minutes), the resulting mixture wasstirred for 1 hour at -78 degrees centigrade. The organocerium reagent,cerium dichloride trimethylsilylacetylide, was transferred over 45minutes into a solution of 6.36 g (41.3 mmol) of methyl5-oxocyclohex-2-ene-1-carboxylate in 80 mL of THF at -78 degreescentigrade. The resulting mixture was stirred for 1 hour more at -78degrees centigrade and the reaction mixture was poured without warminginto 400 mL of 10 percent ammonium chloride solution at 0 degreescentigrade. The resulting mixture was extracted with four 150-mLportions of ether. The combined organic extracts were washed with 200 mLof saturated aqueous sodium chloride solution and dried over sodiumsulfate. Evaporation of the solvent yielded 10.04 g (41.1 mmol, 99.5percent) of methylcis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate, anoil.

IR(CH₂ Cl₂): 3585 (COH), 2160 (C═C), 1721 (COOCH₃), 1653 (C═C) cm⁻¹.

¹ NRM(CDCl₃): delta values 5.9-5.7 (m, 2H, CH═CH), 3.7 (s, 3H, COOCH₃),3.3 (m, 1H, CHCOO), 2.6 (s, 1H, OH), 2.5 (dd, 1H, C═CCH₂), 2.4 (dd, 1H,C═CCH₂), 2.2 (m, 2H, CH₂), 0.2 (s, 9H, Si(CH₃)₃).

¹³ C NMR (CDCl₃): delta values 174.0, 125.3, 123.4, 108.2, 87.4, 65.7,51.9, 41.2, 39.1, 37.6.

MS, m/e (relative intensity): 252.2116 [M]⁺ (0.72), 237.0949 [M-CH₃ ]+(29), 140.0657 (61). HRMS calcd for C₁₃ H₂₀ O₃ Si: 252.1181.

Anal. Calcd for C₁₃ H₂₀ O₃ Si: C, 61.86, H, 7.99. Found: C, 62.10, H,8.13,

Example 4 Methylcis-(2,3-Epoxy-5-hydroxy)-5-(trimethylsilylethynyl)cyclohexane-1-carboxylate

A solution of tert.-butyl hydroperoxide (25.5 mL, 76.66 mmol 3.0M) in2,2,4-trimethylpentane was added to a stirred mixture of molybdenumhexacarbonyl (207 mg, 0.784 mmol), methylcis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate (5g, 19.16 mmol) and 4A activated molecular sieves) in 100 mL of benzene.The mixture was then heated under reflux for 18 hours and (CH₃)₂ S wasadded. The mixture was filtered and the residue washed with ethylacetate (100 mL). The combined organic solutions were washed with water(3×100 mL) and the aqueous layer was re-extracted with CH₂ Cl₂ (2×100mL). The combined organic layers were dried over sodium sulfate.Evaporation of the solvent gave the crude product (4.5g) as an oil.Flash chromatography of the oil (3:1 hexanes/ethyl acetate v/v) gavecrystalline methylcis-(2,3-epoxy-5-hydroxy)-5-(trimethylsilylethynyl)cyclohexane-1-carboxylate(0:4.3 g, 84 percent), mp. 74.1 to 74.6 degrees centigrade.

IR(KBr): 3360 (OH), 2160 (C═C), 1732 (C═O), 1260, 845 cm⁻¹.

¹ H NMR (CDCl₃): 3.8 (s, 3H, COOCH₃), 3.5 (m, 1H, CHCOO), 3.3 (m, 2H,HCOCH), 2.4 (dd, 1H, CH₂), 2.3 (s, 1H, OH), 2.0 (d, 1H, CH₂), 1.85 (m,2H, CH₂), 0.17 (s, 9H, C═CSi(CH₃)₃).

¹³ C NMR (CDCl₃): 172.45 (COO), 107.43 (SiC═C), 89.47 (C═C), 66.26,52.2, 51.80, 50.71, 40.92, 38.26, 31.03, 0.20 (Si(CH₃)₃).

MS m/r (relative intensity): 253.0897 (21.8) [M-CH₃ ]⁺, 236.0871 (38.2)[M-CH₃ OH]⁺, 191. 0035 (19.3), 159.0715 (16.6). Calcd for C₁₃ H₂₀ O₄ Si:253.0896.

Anal. Calcd for C₁₃ H₂₀ O₄ Si: C, 58,18, H, 7.51. Found: C, 58.09, H,7.65.

Example 5 Methylcis-3,5-Dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylate

A solution of 92.8 mg (0.345 mmol) of methylcis-(2,3-epoxy-5-hydroxy)-5-(trimethylsilylethynyl)cyclohexane-1-carboxylateand 52.5 mg (0.345 mmol) of 1,8-diazabicylo-[5.4.0]-undec-7-ene in 10 mLof methylene chloride was stirred for 2 hours at room temperature. Thesolvent was removed by evaporation and the residue was dissolved in aminimum amount of methylene chloride and filtered through a plug offlash silica gel (1:1 hexanes/ethyl acetate v/v). Evaporation of thesolvent yielded methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylate,a colorless oil, which crystallized on standing, mp 89.8 to 90.8 degreescentigrade.

IR (CH₂ Cl₂): 3310 (OH, 2158 (C═C), 1721 (COOCH₃), 1653 cm⁻¹.

¹ H NMR (CDCl₃): delta values 7.1 (s, 1H, C--CH), 4.4 (m, all couplingsless than 2 Hz, 1H, CCH(OH)), 3.8 (s, 3H, COOCH₃), 3.0-3.4 (m, 1H, OH),2.9-2.8 (dd, 2H, CH₂), 2.6 (s, 1H, OH), 2.5-2.2 (dd, 2H, CH₂), 0.17 (s,9H, C--CSi(CH₃)₃).

¹ H NMR (D₆ DMSO): delta values 7.1 (s, 1H, C═CH), 6.2 (2,1H, OH), 5.6(d, 1H, OH), 4.7 (bs, 1H, CCHH(OH)), 4.0 (s, 3H, COOCH₃), 3.0 (d, J=17Hz, 1H, C═CCH equatorial), 2.6 (d, J=17 Hz, 1H, C═CCH axial), 2.5 (m,1H, (HO)CCH axial), 1.9 (dd, J=10, 10 Hz, 1H (HO)CCH axial).

¹³ C NMR (CDCl₃): 167.20 (C═O), 138.88, 127.60, 108.0, 88.52, 66.04,61.62, 51.92, 41.74, 38.87, 0.228.

Anal. Calcd for C₁₃ H₂₀ O₄ Si: C, 58.18; H, 7.51. Found: C, 58.24; H,7.65.

Example 6 Addition of Nitromethane to Methylcis-3,5-Dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1carboxylate

(i) Methylcis-3,5-dihydroxy-5-trimethylsilylethynylcyclohex-1-ene-1-carboxylate(5.91 g, 22.0 mmol) was added in one portion to a mixture ofnitromethane (12.2 g, 44.0 mmol) and DBU (6.7 g, 22.0 mmol) in 30 mL ofdimethyl sulfoxide (DMSO). The mixture was stirred at room temperaturefor 15 hours and then neutralized to pH 6 with about 20 mL of 6M HCl.

The resulting mixture was extracted with four 100-mL portions of ethylacetate. The organic phase was washed with 30 mL of saturated aqueoussodium chloride solution and dried over sodium sulfate. Evaporation ofthe solvent gave a crude oil product (10.0 g), which contained someDMSO.

Flash chromatography in ethyl acetate/hexanes (3:7 v/v) gave methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylecyclohexane-1beta-1-carboxylate(trans isomer, 0.8321 g, 2.5 mmol, 11.5 percent); methyl3alpha,5alpha-dihydroxy-5beta-trimethylsilylethynyl-2beta-nitromethylcyclohexane-2beta-carboxylate(the cis isomer, 1.95 g, 5.9 mmol, 26.9 percent); methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2alpha-nitromethylcyclohexane-1beta-carboxylate(trans desilylated isomer, 1.52 g. 5.9 mmol, 26.9 percent); methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2beta-nitromethylcyclohexane-1beta-carboxylate(cis desilylated isomer, 1.28, 5.0 mmol, 22 percent). The overall yieldof nitro adducts was 88 percent.

(ii) Nitromethane (8 mL, 112 mmol) was added to a slurry of sodiumhydride (2.4 g, 56 mmol, 50 percent in mineral oil) in 50 mL of dryDMSO. The mixture was cooled as necessary to maintain an internaltemperature of 20 degrees centigrade and stirred slowly for 1 hour.Methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cylohex-1-ene-1carboxylate(3.0 g. 11.2 mmol) was added in one portion and the mixture was stirredfor 24 hours at room temperature. To the resulting mixture was added 3mL of conc HCl in ice. Additional HCl was added until the pH reached 7.The mixture was extracted with four 150-mL portions of ether, washedwith 100 mL of saturated aqueous sodium chloride solution, dried oversodium sulfate and evaporated to give 3.39 g of residue, which containedsome DMSO (TLC).

Flash chromatography in ethyl acetate/hexanes (3:7 v/v) gave 2.12 g ofproduct, characterized as a mixture of diastereomeric methyl3,5-dihydroxy-5-(trimethylsilylethynyl)-2-nitromethylcyclohexane-1-beta-carboxylates.

Trans isomer (1,021 g, 25.8 percent), methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate:

IR (CH₂ Cl₂): 3421, 2958, 2161, 1737, 1558 cm⁻¹.

¹ H NMR (CDCl₃): delta values 4.7-4.6 (dd, 1H, CH₂ NO₂), 4.0-4.1 (m, 1H,CHOH), 3.8 (bs, 2H, OH), 3.7 (s, 3H, COOCH₃), 2.8-2.9 (ddd, J=4, 12, 12Hz, CHCOOCH₃). 2.5-2.6 (m, 1H, CHCH₂ NO2), 2.3-2.4 (m, 2H, CH₂equatorial), 2.0 (dd, J=12, 12 Hz, 1H, CH₂ axial), 1.9 (dd, J=12, 3 Hz,1H, CH₂ axial), 0.1 (s, 9H, Si(CH₃)₃).

¹³ C NMR (CDCl₃): delta values 173, 128, 106, 87, 75, 67.1, 66.8, 52,41.5, 41.2, 36.7, 0.3.

Cis isomer (1.101 g, 19.8 percent), methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2beta-nitromethylcyclohexane-1betacarboxylate:

IR (CH₂ Cl₂): 3423, 2956, 2160, 1739, 1556 cm⁻¹.

¹ H NMR (CDCl₃): delta values 4.6 (dd, 1H, CH₂ NO₂), 4.1 (m, 1H, CHOH),3.7 (s, 3H, COOCH₃), 2.9 (bs, 2H, OH), 2.0-2.2 (mc, 4H, CH₂), 0.2 (s,9H, Si(CH₃)₃).

¹³ C NMR: delta values 173, 128, 106, 89, 74, 67.7, 67.1, 52, 41, 37,30, 0.2.

Anal. Calcd for C₁₄ H₂₂ O₆ NSi: C, 51.20, H. 6.75, N, 4.26. Found: C,51.20; H, 7.19: N, 4.17.

Example 7

Addition of Nitromethane to Methylcis-(2,3-Epoxy-5-hydroxy)-5-(trimethylsilylethynyl)cyclohexane-1carboxylate

Nitromethane (4.2 g, 68 mmol) was added to a solution of 50 mL of DMSOand 5.2 g, (34 mmol) of DBU in 50 mL of DMSO. The mixture was stirredfor 5 minutes, after which 1.8 g (6.8 mmol) of solid methylcis-2,3-epoxy-5-hydroxy-5-(trimethylsilyl-ethynyl)cyclohexane-1-carboxylate was added in one portion. The reactionwas followed by TLC, using 1:2 v/v ethyl acetate/hexanes as eluant.After 2 hours, all of the epoxide had been consumed and a new spot,corresponding to diol appeared. After 16 hours, TLC showed that four newproducts and no starting materials or diol was present.

The reaction mixture was poured into 100 mL of cold 5 percent HClsolution and extracted with four 50-mL portions of ether and with 100-mLof saturated aqueous NaCl solution and dried over sodium sulfate. Theether was evaporated to yield 0.66 g of an oil, which was separated byflash chromatography (1:2 v/v ethyl acetate/hexanes) to yield methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate(0.28 g, 12.5 percent, trans nitro diol) and methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilyl-ethynyl)-2beta-nitromethylcyclohexane-1beta-carboxylate(0.31 g, 13.8 percent, cis nitro diol).

The aqueous phase was reextracted with methylene chloride and dried oversodium sulfate. Evaporation of solvent gave 0.52 g of an oil, separatedby flash chromatography (1:1 v/v ethyl acetate/hexanes) into twodesilylated nitroadducts, methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2alpha-nitromethylcyclohexane-1beta-carboxylate(0.25 g, 12.4 percent, trans desilylated isomer) and methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2beta-nitromethylcyclohexane-2beta-carboxylate(0.19 g, 9.4 percent, cis desilylated isomer).

Example 8 Acetonide of Methyl3alpha,5alpha-Dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxyate

A mixture of 2-methoxypropene (260 microL, 3.6 mmol), trans nitro diol(methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate,1.2 g, 3.6 mmol) and pyridinium tosylate (10 mg, 0.036 mmol) in 100 mLof benzene was stirred for at room temperature for 15 minutes. After 260microL (3.6 mmol) of additional 2-methoxypropene was added, theresulting mixture was heated under reflux for 5 minutes. The resultingsolution was cooled and washed with 30 mL of saturated aqueous sodiumbicarbonate solution with 30 mL of saturated aqueous sodium chloridesolution and dried over sodium sulfate. Evaporation of solvent yielded1.22 g (3.22 mmol, 89 percent) of acetonide as an oil.

1R (neat ATR): 2990, 2164, 1735, 1556 cm⁻¹.

¹ H NMR (CDCl₃): delta values 4.6-4.5 (dd, 1H, CHNO₂), 4.4-4.35 (dd, 1H,CHNO₂), 4.25-4.3 (m, 1H, CHOC), 3.7 (s, 3H, COOCH₃), 3.0 (ddd, J=3, 4,15 Hz, 1H, CH equatorial), 2.85 (ddd, J=5, 12, 12 Hz, 1H, CHCOOCH₂), 2.6(m, 1H, CHCH₂ NO₂), 2.4 (ddd, J=3, 5, 15 Hz, 1H, CH equatorial), 1.8 (m,2H, CH axials), 1.6 (s, 3H, CH₃), 1.4 (s, 3H, CH₃), 0.16 (s, 9H,Si(CH₃)₃).

¹³ C NMR (CDCl₃): delta values 173.6, 106.3, 97.9, 88.5, 75.2, 66.3,65.4, 52.0, 41.8, 41.5, 38.7, 33.0, 31.4, 30.3, 0.3.

HRMS, m/e (relative intensity): 354.1366 [M-CH₃ ]⁺ (11.3), 294.1158[M-OC₃ H₆ ]⁺ (5.4), 264.1184 [294-NO₂ ]⁺ (46.5), 73.0472 [TMSi]⁺ (100);calcd for C₁₆ H₂₄ N O₆ Si 354.1373.

Example 9 Oxidation of 1-hydroxy-5-methoxy-naphthalene to1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene by Iodobenzene Diacetate

A solution of 15.5 g (48 mmol) of iodobenzene diacetate and 22 g ofNaHCO₃ in 100 mL of methanol/trimethyl orthoformate (1/1) was stirred atroom temperature for 30 minutes. To this mixture a solution of 3.74 g of1-hydroxy-5-methoxynaphthalene (21.5 mmol) in 250 mL of methanol wasadded dropwise. The color of the mixture changed from orange to greenishyellow over 2 hours at room temperature.

Ether (150 mL) was added to the mixture, and then sat. NaHCO₃ (75 mL).The aqueous washings were back extracted with ether (75 mL×3). Thecombined ethereal extracts were washed with saturated aqueous sodiumchloride solution and dried over sodium sulfate. The solution wasevaporated to give 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene.

Flash chromatography of this product with elation using EtOAc:Hex 1:1yielded 3.70 g (74 percent) of crystals of1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene, mp 62-63 degreescentigrade.

¹ H NMR (CDCl₃): delta values 7.7 (d, 1H, aromatic), 7.52 (t, 1H,aromatic), 7.16 (d, 1H, aromatic), 6.80 (m, 2H, HC═CH), 3.92 (s,3H,OCH₃), 3.14 (s, 6H, (OCH₃)₂) (2OCH₃).

UV (MeOH): maximum wavelength: 222 nm.

IR (neat): 1672, 1635, 1589, 1580, 1300, 1178, 1068, 1031 cm⁻¹.

Example 103-[(2beta-Carbomethoxy-4beta-ethynyl-4alpha-6alpha-(di-O-isopropylidenyl)-cyclohexanyl-1-yl)]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4tetrahydronaphthalene

A solution of 0.904 g (3.0 mmol) of trans nitroacetonide (acetonide ofmethyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate),1.34 g (5.7 mmol) of 1.4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene and750 microL (5 mmol) of DBU in 0.5 mL of acetonitrile was stirred for 5days at room temperature. Methylene chloride (5 mL) was added to themixture and the solution was chromatographed on a column packed with 150g of silica gel (5 cm column, 30:70 v/v ethyl acetate/hexanes slurry).The material on the column was eluted with 400 mL of 30:70 v/v ethylacetate/hexanes. After the nitro acetonide was eluted, as followed byTLC (iodine development), the chromatographic separation was continuedwith 1000 mL of 50:50 v/v ethyl acetate/hexanes.

Evaporation of the solvent from the various fractions gave recoverednitro acetonide (0.66 g, 2.2 mmol), recovered dimethyl ketal (1.03 g,4.4 mmol) and product,3-[(2beta-carbomethoxy-4beta-etnyny-4alpha,6alpha-(di-O-isopropylidenyl)-cylohexanyl-1-yl)-nitromethyl]-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene(0.274 g, 0.51 mmol, 62 percent based on recovered acetonide) as an oilymixture of diasteromers.

IR (ATR thin film): 1733 (COOMe), 1686 (C═O), 1588, 1579 (NO₂) cm⁻¹.

¹ H NMR (CDCl₃): delta values 7.6 (d, 1H, Ar), 7.4 (dd, 1H, Ar), 7.1 (d,1H, Ar), 5.3-5.0 (d, 1H, CHNO₂), 4.4-4.0 (m, 1H, CHOC), 3.7 (s, 3H,ArOCH₃), 3.5 (s, 3H, COOCH₃), 3.3-2.8 (complex group of overlappingprotons, 10H), including (COCH₃ ketal, 3.2, 3H, and 3.1, 3H), (O═CCH2,2H), and (CHCOOCH₃, 1H), (HCCHNO₂, 1H)), 2.5 (s, 1H, C═CH), 2.5 (d, 1H,CH₂), 2.2 (d, 1H, CH₂), 1.8 (d, 1H, NO₂ CHCH), 1.6-1.5 (m, 2H, CH₂, 1.5(s, 3H, CCH₃), 1.2 (s, 3H, CCH₃).

¹³ C NMR (CDCl₃): mixture of two diastereomers, (195.4, 195.1), (174.3,173.2), (157.6, 157.5), (134.3, 134.0), (130.3, 130.2), (125.3),(120.05, 120.0), (117.2, 117.15), (101.6, 101.6), (97.9, 97.7), (86.1,85.10), (84.48, 84.42), (72.6, 72.5), (66.0, 65.9) (64.5, 64.4), (55.9),(52.2, 51.6), (50.56, 50.46), (50.4, 50.1), (43.4 43.1), (42.8, 42.7),(42.0, 40.7), (39.77, 39.70), (35.8, 35.6), (32.7, 32.6), (31.2, 31.1),(30.05, 29.9).

Example 119beta-Ethynyl-5,5-dimethoxy-12-hydroxy-7alpha,9alpha-di-(O-isopropylidenyl)-4-methoxy-6-nitro-5,5a,6,6a,7,8,9,10,10a-decahydro-11-naphthacenone

Sodium hydride (24 mg, 0.8 mmol) was added in one portion to a solutionof3-[(2beta-carbomethoxy-4beta-ethynyl-4alpha,6alpha-(di-O-isopropylidenyl)-cyclohexanyl-1-yl)]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene(0.380 g, 0.72 mml) and methanol (3 drops) in 25 mL of toluene at 0degrees centigrade. After 15 minutes' stirring, the cooling bath wasremoved. The reaction mixture was stirred for an additional 18 hours atroom temperature and then washed briefly with 10 mL of cold 5 percentHCl. The organic phase was further washed with 5 mL of saturated aqueoussodium bicarbonate solution, with two 10-mL portions of saturatedaqueous sodium chloride solution and dried over sodium sulfate. Thesolvent was evaporated to give 0.260 g of crude oily product, which wasrecrysallized from toluene to yield 0.252 g (0.42 mmol, 71.0 percent) of9beta-ethynyl-5,5-dimethoxy-12-hydroxy-7alpha,9alpha-(di-O-isopropylidenYl)-4-methoxy-6-nitro-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenone,white crystalline solid, mp 234 degrees centigrade (decomp).

IR (ATR thin film): 3320 (C═C--OH), 2260 (C═CH), 1559 (NO₂) cm⁻¹.

¹ H NMR (CDCl₃): delta values 16.2 (s, 1H, C═COH), 7.8 (d, 1H, ArH), 7.6(t, 1H, ArH) 7.1 (d, 1H, ArH), 5.2 (dd, J=1, 3 Hz, 1H, CHNO₂), 4.6 (d,J=4.5 Hz, 1H, CHOC), 3.9 (s, 3H, ArOCH₃), 3.9 (ddd, J=4.5, 13, 13 Hz,1H, O═CCH), 3.5 (d, J=4.5 Hz, 1H, C═C--CHCHNO₂), 3.4 (s, 3H, OCH₃ketal), 3.1 (ddd, 1H, CH₂ equatorial), 3.0 (s, 3H, OCH₃ ketal), 2.9(ddd, J=3, 3, 13 Hz, 1H, CH₂ equatorial), 2.5 (s, 1H, C═CH), 1.8 (d,J=12 Hz, 1H, NO₂ CHCHCO), 1.67 (d, 1H, CH₂ axial), 1.64 (s, 3H, OCCH₃),1.5 (dd, J=12, 12 Hz, 1H, CH₂ axial), 1.3 (s, 3H, OCCH₃).

¹³ C NMR (CDCl₃): HETCOR-DEPT 196.9 (C═O), 172.6 (ArC═COH), 157.2 (ArCJCOH), 133.0 (Ar), 130.6 (ArH), 122.8 (Ar), 119.4 (ArH), 115.7 (ArH),101.6, 101.3, 98.4, 85.2 (C═CH), 79.9, 72.1 (CHNO₂), 69.5 (CHOC), 66.3,55.8 (ArOCH₃), 52.5 (COCH₃), 51.4 (COCH₃), 46.0 (NO₂ CCHCO), 44.8(CHCNO₂), 40.2 (CH₂), 35.3 (CHC═O), 34.3 (CH₂), 30.8 (OCCH₃), 30.4(OCCH₃).

UV-Vis: maximum wavelengths 350 (11200), 344 (11900) 341(12300),232(10678).

Example 129beta-Acetyl-7alpha,9alpha,12-trihydroxy-4,5-dimethoxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone

Sulfuric acid (1.5 mL, 3M) was added to a solution of 212 mg (0.42 mmol)of9beta-ethynyl-5,5-dimethoxy-12-hydroxy-7alpha,9alpha-(di-O-isopropylidenyl)-4-methoxy-6-nitro-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenone in 20 mL of THF. The solutionimmediately turned a bright yellow color. To the resulting solution wasadded 24.5 mg (0.11 mmol) of HgO. The resulting mixture was stirred for4 hours at room temperature, cooled to 0 degrees centigrade andneutralized to pH 6 with 0.5 g of potassium hydroxide in 3 mL of water.The mixture was poured into 20 mL of water and extracted with four 20-mLportions of ethyl acetate. The combined organic layers were washed withtwo 20-mL portions of water and with 20 mL of saturated aqueous sodiumchloride solution and dried over sodium sulfate. The solvent was removedby evaporation to yield 0.176 g (0.39 mmol, 93.2 percent) of9beta-acetyl-7alpha,9alpha,12-trihydroxy-4,5-dimethoxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone, yellow solid. Product recrystallized fromacetone gave fine yellow needle crystals, mp 186 degrees centigrade(decomp).

IR (ATR thin film): 3427 (OH), 1711 (C═O), 1628, 1591, 1554 (NO₂) cm¹.

¹ H NMR (THF D₄): delta values 14.3 (s, 0.5H, ArOH), 8.0 (d, 1H, ArH),7.5 (dd, 1H, ArH), 7.2 (d, 1H, ArH),m 6.4 (d, 1H, CHNO₂), 5.5 (bs, 0.5H,OH), 5.0 (bs, 0.5H, OH), 4.6 (m, 1H, CHOH), 3.9 (s, 2H, ArOCH₃ D-ring),3.7 (s, 3H, ArOCH₃ C-ring), 3.7 (ddd, 1H, COCH), 2.6 (ddd, 1H, CH₂equatorial), 2.5 (ddd, 1H, CH₂ equatorial), 2.3 (s, 3H, COCH₃), 1.8 (m,1H, NO₂ CHCH), 1.8-1.7 (m, 2H, CH₂ axials partly obscured by THF peak).

¹³ C NMR (THF D₄): delta values 211.3 (C═O), 206.7 (C═O), 160.0, 157.3,128.5, 122.4, 117.6, 117.5, 112.5, 112.4, 110.1, 81.9, 80.4, 69.87,69.83, 62.7, 56.6, 46.0, 39.1, 36.2, 35.9, 35.8.

UV-Vis (MeOH) maximum wavelengths: 339, 321, 262, 220 nm.

Example 139beta-Acetyl-7alpha,9alpha-dihydroxy-4-methoxy-6-nitro-5,6,6a,7,8,9,10,10a,11,12-decahydro-5,11-12-naphthacenetrione

Thallium nitrate (55 mg, 0.11 mmol) was added to a solution 50 mg (;0.11mmol) of9beta-acetyl-7alpha,9alpha,12-trihydroxy-4,5-dimethoxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenonein 5 mL of acetone at 0 degrees centigrade. The mixture was brought toroom temperature and stirred for 2 hours. Additional thallium trinitrate(11 mg, 0.02 mmol) was added and stirring was continued for 1 hour. Theresulting solution was poured into 20 mL of water and extracted withthree 25-mL portions of ethyl acetate. The combined organic extractswere washed with two 25 mL portions of water and with 25 mL of saturatedaqueous sodium chloride solution and dried over sodium sulfate. Thesolvent was evaporated to yield 99.5 mg of crude yellow product, anorange solid.

The product, which turned black upon standing, was dissolved in 5 mL of9:1 ethyl acetate/hexanes v/v. After 16 hours, an orange precipitate hadformed. The supernatant was removed by decantation and the resultingsolids dried to give 25 mg (0.06 mmol, 54.5 percent) of9beta-acetyl-7alpha,9alpha-dihydroxy-4-methoxy-6-nitro-5,6,6a,7,8,9,10,10a,11,-12-decahydro-5,11,12-naphthacenetrione,mp 242 degrees centigrade (decomp).

¹ H NMR (acetone D₆): delta values 7.9 (dd, 1H, aromatic), 7.7 (d, 1H,aromatic), 7.6 (d, 1H, aromatic), 6.2 (d, J=4.5 Hz, 1H, CHNO₂), 5.5 (s,0.5, OH), 4.9 (m, 0.5, OH), 4.7 (m. 1H, CHOH), 4.0 (s, 3H, ArOCH₃), 3.5(ddd, J=4, 12, 13, Hz, 1H, COCHCH₂), 2.8 (ddd, J=1, 5, 13 Hz, 1H,COCHCH₂ equatorial), 2.4 (ddd, 1H, COHCH₂ equatorial), 2.3 (s, 3H,COCH₃), 1.9 (m, 1H, NO₂ CHCH partially obscured by acetone quintet).

IR (ATR thin film): 1709 (C═O), 1663, 1665, 1587, 1560 (NO₂) cm⁻¹.

UV-Vis (MeOH) maximum wavelengths: 424 nm 274, 258 nm.

EXAMPLE 147alpha,9alpha-(Di-O-isopropylidenyl)-4,5-dimethoxy-9beta-ethynyl-12-hydroxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone

A catalytic amount of pyridinium tosylate (5 mg) was added to a solutionof 100 mg (0-20 mmol) of the decahydro-11-naphthacenone (example 11) in20 mL of CH₂ Cl₂. The mixture was refluxed for 6 hours while the colorof the solution changed from light to shiny yellow. The reaction mixturewas washed with water (2×20 mL) dried over Na₂ SO₄ and the solvent wasremoved in vacuo. The yellow residue was recrystallized from hexane:ethyl acetate (9:1) to give the octahydro-11-naphthacenone as a mixtureof 2 stereoisomers at C₆ (88 mg, yield 94 percent). The isomer can beseparated by chromatography. Major isomer 85 percent m.p. 243-244degrees centigrade.

IR (KBr) 3262, 1733, 1616, 1572, 1563, 1554, 1501, 1456, 1430, 1382,1276, 1261, 1215 cm⁻¹.

NMR (360 MHz, CDCl₃): major isomer 14.01(s, 1H), 8.12(d, 1H), 7.49(t,1H), 7.02(d, 1H), 6.35(d, J=4 H₂ 1H), 4.73(d, 1H), 3.95(s, 3H), 3.27(m,1H), 2.16(d, 1H), 1.61(s, 3H), 1.30(s, 3H), ppm.; (minor isomer 15percent) 13.34(s, 1H), 8.05(d, 1H), 7.47(t, 1H), 7.05(d, 1H), 6.21(d,J=10.4 H₂ 1H), 4.40(d, 1H), 3.91(s, 3H), 3.71(s, 3H), 3.66(d, 1H),3.12(m, 2H), 2.53(s, 1H), 2.19(m, 2H), 1.67(s, 3H), 1.37 (s, 3H) ppm.

UV Vis. (MeOH) maximum wavelength: 230, 266, 328, 396 nm.

Anal. Calcd. for C₂₅ H₂₅ O₈ N: C, 64.2, H, 5.39, N, 3.00. Found: C,64.9, H, 5.31, N: 3.04.

EXAMPLE 157alpha-9alpha-(Di-O-isopropylidenyl)-9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro7,8,9,10-tetrahydro-5,12-nathacenedione

A solution of 36 mg (0.075 mmol) of the octahydro-11-naphthacenone and60 mg (0.675 mmol) of NaHCO₃ in 10 mL of acetone was treated with asolution of 167 mg (3 mmol) of cerium ammonium nitrate (CAN) and 1 mg ofdichlorodicyanobenzoquinone (DDQ) in 2 mL of acetone added in oneportion at 0 degrees centigrade. The reaction mixture was stirred atroom temperature for 1.5 hours during which the color changed from shinyyellow to orange red, and then 25 mL of CH₂ Cl₂ was added. The mixturewas filtered through over Celite. The organic layer was washed withsaturated NaCl solution (2×20 mL), dried over Na₂ SO₄, and evaporated togive the tetrahydro-5,12-naphthacenedione as a red crystals (29 mg, 86percent). mp greater than 258 degrees centigrade (decomp).

IR (KBr) 3306, 1620, 1588, 1529, 1491, 1369 cm⁻¹.

¹ H NMR (360 MHz, CD₂ Cl₂ 15.00(s, 1H), 7.19 (d, 1H) 7.57(t, 1H),7.36(d, 1H), 4.50(m, 1H), 4.00(s, 3H), 3.12(m, 2H), 2.65(m, 2H), 2.57(s,1H), 1.68(s, 3H), 1.37(s, 3H) ppm.

UV-Vis. (MeOH) maximum wavelength: 223, 240, 248, 358, 440 nm; (CHCl₃)246, 370, 390, 416, 436 nm.

Example 16 6-Desoxy-6-nitrodaunomycinone

A solution of 12 mg of (0.027 mmol) of thetetrahydro-5,12,-naphthacenedione in 2.5 mL of tetrahydrofuran wastreated with 150 microL of H₂ SO₄ (3M) and then 5 mg of mercuric oxideat 0 degrees centigrade and stirred at room temperature for 24 hours.The turbid solution was neutralized with NaHCO₃ to pH 8, and extractedwith CH₂ Cl₂ (10×) 15 mL). The extract was dried over Na₂ SO₄, andevaporated to yield 6-desoxy-6-nitrodaunomycinone as a red solid (7 mg,61.4 percent). Flash chromatography on silica (60-200 mesh) eluting with70:25:5(ethyl acetate:hexane:MeOH) afforded 2 mg of the pure mycinone asred crystals.

IR (CHCl₃), 3364, 1708, 1662, 1615, 1591, 1525, 1499, 1446, 1278, 1336cm⁻¹.

¹ H NMR (360) MHz, CD₂ Cl₂ 15.15(s, 1H), 8.06 (d, 1H), 7.82(t, 1H),7.42(d, 1H), 5.44(m, 1H, OH), 4.61(s, 1H), 4.09(s, 3H), 3.79(m, 1H, OH),3.21(d, 1H), 3.00(d, 1H), 2.40(s, 3H), 2.30(d, 1H), 2.21(m, 1H ) ppm.

UVVisi maximum wavelengths: (CHCl₃) 245, 250, 420, 446 nm; (MeOH) 360,385, 418, 441, 466 nm.

Example 176-Amino-9beta-ethynyl-4-methoxy-7alpha,9alpha,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione

A solution of 15 mg (0.033 mmol) of the tetrahydro-5,12-naphthacenedionefrom example 15 and 96 mg (0.70 mmol) of NaOOCCH₃ ;3H₂ O in 2 mL of CH₃OH was treated with SnCl₂ H₂ O (183 mg, 0.88 mmol), in 3 portions over a90 min. at room temperature. During the addition the color of thesolution changed to yellow. After the SnCl₂ was added, the mixture wasstirred for 1 h, and the solvent was evaporated. A mixture of 15 mL ofCH₂ Cl₂ and 15 mL of saturated aqueous NaHCO₃ was added and the mixturewas stirred for 30 min. During the stirring the color changed to pinkand CO₂ was evolved.

The mixture was filled through Celite and extracted with CH₂ Cl₂ (3×20mL). The combined organic layers were washed with saturated aqueousNaCl, dried (Na₂ SO₄), and evaporated to yield 14 mg of yellow solid.TLC showed that this was a mixture of 2 compounds. Flash chromatographyusing elution with hexane: ethyl acetate: MeOH (75:20:5) gave twocompounds, the 6-desoxy-6-nitro starting material (6mg), and6-amino-9beta-ethynyl-4-methoxy-5,7alpha,9alpha,11,12-pentahydroxy-7,8,9,10-tetrahydronaphthacene(7.5 mg) as shining yellow crystals (mp, 234-238 degrees centigrade).NMR: 14.1(s, 1H,OH)O),13.4(s,2H,OH),8.1(d,1H),7.7(t,1H),7.2(d,1H),5.0(m, 1H),4.25(m, 1H,OH),4.04(s,H),3.62(m,2H,NH₂),3.15(m1H,OH),2.95(q,2H), 2.55(s,H,C═CH),1.96(m,2H).ppm.

FT-IR (KBr) 3647, 3375,3289, 1671, 1634, 1601, 1582 cm⁻¹.

UV-Vis (CHCl₃) maximum wavelengths 446,422,274,250 nm. A saturatedsolution of 17.5 mg (0.032 mmol ) ceric ammonium nitrate in acetone wasadded at 0 degrees centigrade to pentahydroxynaphthacene (7mg, 0.016mmol) and NaHCO₃ (10 mg) in 2 mL of acetone. The reaction mixture wasstirred for 5 h at room temperature and then filtered through Celite andextracted with CH₂ Cl₂ (7×10 mL). Evaporation yielded mg of the aminotrihydroxy-5,12-naphthacenone as purple red crystals.

¹ H NMR (CD₂ Cl₂), 14.80(s,1H,OH), 8.10 (d,1H),7.85(t,1H),7.42(d,1H),5.35(d,1H),4.30(d,1H,OH), 4.09 (s,3H),3.57(m,2H),3.35(m,1H,OH),3.15(m,2H),2.55(s, 1H), 1.95(m,2H)ppm.

UV-Vis (CHCL₃ ) maximum wavelength: 498, 442, 313, 269 nm.

FT-IR(KBr) 3644, 3277, 1671, 1631, 1580 cm⁻¹.

Example 18 Daunomycinone

A solution of 7 mg (0.018 mmol) of the amino-5,12-naphthacenedione and 1mg of pyridinium tosylate in 2 mL of dimethoxyethane was treated with 15microL of isoamylnitrite. As the mixture was stirred at room temperaturea purple precipitate formed, and 0.5 mL of 0.01N HCL was added; afterstirring had been continued for 5 h, the visible spectrum of the mixtureshowed absorption at 515 nm. Then HgO (40 mg, 0.18 mmol), was added andstirring was continued for 24 h. The mixture was filtered throughCelite, extracted with CH₂ Cl₂ (15×10 mL) and evaporated to yield 10 mgof red solid. Flash chromatography with elution with ethylacetate:hexane:MeOH((90:5:5), followed by recrystalization from CHCl₃gave 3 mg of daunomycinone (mp 217-221 degrees centigrade).

¹ H-NMR (CD₂ Cl₂, 360 MHz), 14.22 (s, 1H), 13.47(2,1H), 8.21(d,1H), 8.00(t,1H), 7.61 (d,1H), 5.48 (m,1H), 4.23 (s,3H), 4.07 (s,3H), 3.95 (d,1H), 3.10 (m,2H), 2.57 (s,3H), 2.30 (m,2H) ppm.

FT-IR (CH₂ Cl₂) 3540, 3053, 2927, 1712, 1616, 1578, 1420 cm³¹ 1.

UV-Visi (MeOH) maximum wavelength: 532, 495, 476, 287, 253, 234nm.

Example 194,5-dimethoxy-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-11-imino-6-nitro-6,6a,7,8,9,10,10a,11-octahydronaphthacene,

The nitrooctahydro-11-naphthacenone (10 mg, 0.021 mmol) was added to 25mL of methanol which had been saturated with ammonia at 0 degrees C. Thereaction mixture was stirred at room temperature with continued bubblingof NH₃ for 2 h (hours). The flow of ammonia was stopped; the reactionflask was sealed and stirring was continued at room temperature for 24h. The color of the solution changed from yellow to brown. The reactionmixture was evaporated and the residue was flash chromatographed (60-200mesh silica). Elution with ethyl acetate:hexane (25:75) gave4,5-dimethoxy-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-11-imino-6-nitro-6,6a,7,8,9,10,10a,11-octahydronaphthacene,as yellow needles (9 mg, 0.018 mmol, 90 percent), m.p: 236-237 degreesC. (210 degrees C., dec.); ¹ H NMR (500 MHz, CDCl₃, ppm), 14.6 (b, 1H,Ar--OH), 8.2 (d, 1H, Ar--H), 7.4 (t, 1H, Ar--H), 7.1 (d, 1H, Ar--H) 6.9(s, b, 1H, NH), 6.3 (d, J=3.2 Hz, 1H, H--CNO₂), 4.7 (d, J=4.5 Hz, 1H, H₇), 4.0 (m, 1H, H_(10a)), 3.96 (s, 3H, OCH₃). 3.7 (s, 3H, OCH₃), 3.1 (dt,J_(gem) =14.8 Hz, J_(H7-H8e) =4.5 Hz, 1H, H_(8e)), 2.7 (dt, J_(gem)=14.8 Hz, J_(H7-H10e) =12.8 Hz), 2.6 (s, 1H, C═CH), 2.0 (dd, J_(6a-10a)=12.3 Hz, J_(6a-6) =3.2 Hz, 1H, H_(6a)), 1.7 (q, 2H, H_(10ax), H_(8a)),1.66 (s, 3H, CH₃), 1.3 (s, 3H, CH₃); ¹³ C NMR (125 MHz, CDCl₃, ppm),176.3, 171.5, 156.0, 142,8, 134.9, 127.2, 122.5, 119.5, 118.5, 113.0,103.3, 98.6, 84.9, 81.7, 72.7, 68.6, 66.0, 61.7, 56.5, 46.0, 40.8, 34.2,30.6, 30.5; FT-IR (KBr neat, cm⁻¹), 3419, 3284, 2964, 2160, 1554, 1539,1467; UV-Vis (CH₃ OH, nm) 224 (15779), 273 (16300), 328 (3291), 428(7854), 448 (7168); FAB-MS: 467 (M+1,45), 420 (100), 307 (15), 154 (100,136 (85).

Example 2011-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedione

Cerium ammonium nitrate (18 mg, 0.035 mmol) and a catalytic amount ofdichlorodicyanobenzoquinone (DDQ, 0.1 mg) and 20 mg of NaHCO₃ were addedto the nitroiminonaphthacene (4 mg; 0.0086 mmol) in 1 mL wet THFsolution. The reaction mixture was stirred at room temperature for fourhours until TLC indicated that all of the starting material had reacted.The color of the solution had changed from deep yellow to red. Thereaction mixture was filtered, and the solvent was evaporated. Flashchromatography of the residue involving elution with ethylacetate-hexane (25:75) yielded11-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12naphthacenedione(3.4 mg, 0.0076 mmol, 89 percent) reddish needles: m.p. 242-244 degreesC. (dec.); 1H NMR (500 MHz, CDCl₃, ppm), 8.0 (d, 1H, Ar--H), 7.7 (t, 1H,Ar--H), 7.3 (d, 1H, Ar--H), 6.9 (b, 2H, NH₂), 5.0 (t, J=2.82 Hz, 1H,H--C--O), 4.0 (s, 3H, OCH₃), 3.1 (dd, 1H, J_(gem) =16.9 Hz, H_(10e)),3.0 (dt, 1H, J_(gem) =16.5 Hz, J_(8e-7) =2.82 Hz, H_(8e)), 2.7 (d, 1H,H_(10a), J_(gem) =16.9 Hz), 2.65 (s, 1H C═CH), 2.1 (dd, 1H, J_(gem)=16.9Hz, H_(8a)), 1.6 (s, 3H, CH₃), 1.1 (s, 3H, CH₃); ¹³ C NMR (125 MHz,acetone-d₆, ppm), 181.0, 179.1, 148.3, 143.0, 136.5, 133.9, 133.7,123.6, 118.5, 117.2, 116.4, 111.7, 98.1, 85.1, 71.6, 67.0, 64.2, 55.7,39.4, 32.4, 30.4, 29.2, 28.9, 28.8; FT-IR (KBr neat, cm⁻¹), 3440, 3301,2987, 2929, 2854, 2160, 1660, 1635, 1583, 1540, 1467; UV-Vis (CH₃ OH,nm), 230 (11872), 372 (1314), 382 (1316), 474 (2666). The same productwas obtained in 90 percent yield by refluxing the nitroiminonaphthancenein O₂ /DMF overnight. Chromatography was not needed.

Example 21 11-amino-6,11-didesoxy-6-nitrodaunomycinone

A solution of 10 mg (0.025 mmol) nitroaminonaphthacenedinoe in THF (2mL) was treated with mercuric oxide (30 mg) and 1 mL of 1N H₂ SO₄. Thereaction mixture was stirred at room termperature for 24 hours and thenacidified to pH 1. The reaction mixture was extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with saturatedaqueous sodium chloride (30 mL) and dried over anhydrous sodium sulfate.The solvent was evaporated to give 10 mg crude product. FlashchromatograPhY using 50 percent ethyl acetate and hexane as elutent gave5 mg (55 percent) of 11-amino-6,11-didesoxy-6-nitrodaunomycinone as anorange solid; m.p. 274-275 degrees; ¹ H NMR (500 MHz, DMSO-d₆, ppm),7.92 (d, 1H, Ar--H), 7.85 (t, 1H, Ar--H), 7.60 (s, 2H, NH₂), 7.55 (d,1H, Ar--H), 6.00 (s, 1H, OH), 5.60 (d, 1H, OH), 4.6 (m, 1H, H₇), 4.0 (s,3H, OCH₃), 3.0 (d, 1H, H_(10e)), 2.6 (d, 1H, H_(10a)), 2.4 (dd, 1H,H_(8e)), 2.35 (s, 3H, CH₃), 2.0 (dd, H, H_(8a)); ¹³ C NMR (125 MHz,dmso-D₆, ppm), 211.1, 183.7, 181.5, 159.6, 149.6, 145.4, 23.9; 135.0,132.8, 125.4, 120.8, 118.6, 117.7, 115.0, 110.0, 76.4, 65.8, 56.3, 40.0,33.5, 23.9; FT-IR (KBr, cm ⁻¹), 3442, 3309 , 1715, 1636, 1616, 1581,1531; UV-Vis (CH₃ OH, nm), 471, 430, 253, 221.

Example 226,11-diamino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione

A solution of 41 mg (0.091 mmol) of the nitroaminonaphthacenedione inmethanol (5 mL) was treated with sodium acetate (120 mg, 0.9 mmol) andthen stannous chloride (167 mg, 0.9 mmol) which was added in threeportions over a period of 90 minutes at room temperature under anitrogen atmosphere. After the mixture had been stirred overnight, itscolor had changed from orange to purple. Then 100 mL of CH₂ Cl₂ and 10mL of saturated aqueous sodium bicarbonate were added. The mixture wasstirred at room temperature for one hour and filtered through Celite.The filtrate was washed with saturated aqueous sodium chloride (2×20mL), and then dried over anhydrous sodium sulfate. The mixture wasseparated by chromatography (60-200 mesh silica treated withtriethylamine and dried at 200 degrees C. for 12 h). Elution withhexane:ethyl acetate (50:50) gave 11 mg of a pink solid and 28 mg of thestarting compound. The pink solid was treated with silver oxide (148 mg0.64 mmol) in 2 mL of ethanol for two hours. The solution was filteredand the filtrate was evaporated to yield a purple solid, purified bychromatography on the basic silica gel. Elution with hexane:ethylacetate (50:50) yielded6,11-diamino-7alpha,9alpha-(di-O)-isopropylidenyl)-9beta-ethyl-4-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione,8 mg (66 percent based on the recovered startingnitroaminonaphthacenedione): mp:206-208 degrees C. (dec); FT-IR (KBr,cm⁻¹), 3442, 3309, 3268, 1637, 1616, 1600, 1581; UV-Vis (CH₃ OH, nm),229 (17338), 249 (14415), 540 (4700); ¹ H NMR (500 MHz, CDCl₃, ppm), 8.0(d, 1Gm, Ar--H), 7.7 (t, 1H, Ar--H), 7.5 (d, 1H, Ar--H), 7.2 (s, 4H,NH₂), 5.0 (t, 1H, H₇), 4.0 (s, 3H, OCH₃), 3.5 (d, 1H, H_(10e)), 2.9 (dt,1H, H_(8e)), 2.8 (d, 1H, H_(10a)), 2.6 (s, 1H, C═CH, h_(8a)), 1.99 (d,1H), 1.6 (s, 3H, CH₃), 1.1 (s, 3H, CH₃).

Example 23 6,11-diamino-6,11-didesoxydaunomycinone

A solution of the diaminonaphthacendione (8 mg, 0.019 mmol) in 1 mL ofTHF was stirred at room temperature under a nitrogen atmosphere and 50mg (0.23 mmol) of HgO and two drops of 2N HCl were added. The reactionmixture was stirred at room temperature under nitrogen atmosphereovernight and filtered through Celite. The filtrate was evaporated andthe residue was purified by chromatography on basic silica (60-200mesh). Elution with ethyl acetate : hexane (70:30) gave6,11-diaminodaunomycinone 3.5 mg (47 percent) as blue solid: ¹ H NMR(500 MHz, CDCl₃, ppm), 8.1 (d, 1H, Ar--H), 7.8 (t, 1H, Ar--H), 7.4 (d,1H, Ar--H), 7.2 (s, 4H, NH₂), 5.2 (t, 1H, H₇), 4.0 (s, 3H, OCH₃), 3.5(b, 2H, OH), 3.2 (d, 1H, H_(10e)), 2.9 (d, 1H, H_(10a)), 2.4 (s, 3H,CH₃), 2.3 (d, 2H, H_(8e)); FT-IR (KBr, cm⁻¹), 3417, 1710, 1652, 1617,1602; UV-Vis (MeOH), 228, 249, 542.

Example 24 11-fluoro-6,11-didesoxy-6-nitrodaunomycinone

Hexafluorophosphoric acid (17 microliters, 60 percent in H₂ O, 0.07mmol) was added at room temperature to a solution of11-amino-6,11-didesoxy-6-nitrodaunomycinone (5 mg, 0.012 mmol) and THF(1 mL) in a waxed flask. The reaction mixture was stirred at roomtemperature for 10 min, then cooled to zero degrees Centigrade, and i-C₅H₁₁ ONO (19.32 mg, 0.07 mmol) was added. The solution was stirred atzero degrees Centigrade for an additional 15 minutes and a reddish solidwas formed. The reddish solid was collected, dried on filter papers anddissolved in triethylamine trihydrofluoride (1 mL). The mixture wasirradiated with ultrasound at 40 degrees Centrigrade for two hours.Ethyl acetate (10 mL) was added. The organic layer was washed with water(2×5 mL) and dried (MgSO₄). TLC showed that there was only one spot(R_(f) =0.45, 30/70 hexane/EtOAc). The solvent was evaporated to give11-fluoro-6,11-didesoxy-6-nitrodaunomycinone (5 mg, 91 percent) as anorange yellow solid: ¹ H NMR (500 MHz, CDCl₃) Delta: 8.0 (d, 1H, Ar--H),7.8 (t, 1H, Ar--H), 7.4 (d, 1H, At--H), 5.2 (t, 1H, C₇ H), 4.9 (bs, 1H,OH), 4.1 (bs, 1H, OH), 4.0 (s, 3H, OCH₃), 3.2 (dd, 1H, C₁₀ H_(e)), 3.1(dd, 1H, C₈ H_(e)), 2.5 (s, 3H, CH₃), 2.4 (dd, 1H, C₁₀ H_(a)), 2.1 (d,1H, C₈ H_(a)); ¹⁹ F NMR (470 MHz, CDCl₃) Delta: 19.0 (s); FT-IR (KBr,cm⁻¹): 3413, 1712, 1656, 1648, 1585, 1539; UV-Vis (CH₃ OH,nm) Lamda max:476 (2889), 379 (1539), 212 (14008).

Example 25 11-amino-6,11-didesoxy-6-nitrodaunomycinone

A mixture of the nitroaminonaphthacenedione(14 mg, 0.031 mmol), HgO (30mg, 0.156 mmol), 2N H₂ SO₄ (0.1 mL) and THF (1 mL) was refluxed for 30minutes to form a pink precipitate. The reaction mixture was cooled toroom temperature and the solid was collected. A solution of the solid inethyl acetate (10 mL) was washed with 1N HCl (10 mL). The aqueous layerwas re-extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with saturated NaCl solution (2×10 mL) and dried (Na₂SO₄). Evaporation of the solvent gave a red solid (12 mg, 91 percent)which recrystallized from EtOAc-hexane to give11-amino-6,11-didesoxy-6-nitrodaunomycinone as a red needles. Anal.Calcd. for C₂₁ H₁₈ N₂ O₈ :C 59.15, H 4.25, N 6.57, Found: C 59.19, H4.60, N 6.39; ¹ H NMR (500 MHz, DMSO-d₆) Delta: 7.92 (d, 1H, ArH), 7.86(t, 1H, ArH), 7.58 (s, 2H, NH₂), 7.55 (d, 1H, ArH), 5.97 (s, 1H, OH),5.63 (d, 1H, OH), 4.60 (t, 1H, C₇ H), 4.0 (s, 3H, OCH₃), 2.95 (d, 1H,C₁₀ H_(e)), 2.64 (d, 1H, C₁₀ H_(a)), 2.35 (s, 3H, CH₃), 2.15 (d, 1H, C₈H_(e)), 1.95 (dd, 1H, C₈ H_(a)); ¹³ C NMR (125 MHz, DMSO-d₆) Delta:211.1, 183.7, 181.5, 159.6, 149.6, 145.4, 136.7, 134.9, 132.8, 125.4,120.8, 118.6, 117.7, 114.9, 109.8, 76.4, 65.8, 56.3, 40.0, 33.5, 23.9;FT-IR (KBr, cm⁻¹): 3442, 3304, 1715, 1636, 1616, 1581, 1531; UV-Vis (CH₃OH, nm) Lambda max: 471, 430, 253, 221.

Example 26

Methyl2alpha,3alpha-expoxy-5alpha-hydroxy-5beta-trimethylsilythynylcyclohexane-1alphacarboxylate.

Activated molecular sieves (4A, 0.5 g) and Ti(i-PRO)4 (16.9 mg, 0.06mmol) were added to a solution of methyl5-hydroxy-5-trimethylsilythynyl-cyclohex-2-enecarboxylate (300 mg, 1.19mmol) in benzene (5 ml). The mixture was stirred for 30 minutes undernitrogen, cumene, hydroperoxide (80%, 0.5 mL, 2.63 mmol) was then addedat 0 degrees Celsius. The reaction mixture was stirred at roomtemperature for 30 hours until TLC showed no starting material remained.The mixture was cooled to 0 degrees Celsius and (CH₃)₂ S (192 mL, 163mg, 2.63 mmol) was added. After the mixture had been stirred at roomtemperature for 30 minutes, it was filtered and the solid residue waswashed with ether (20 mL). The combined organic solutions wereevaporated to give an oil. The crude oil was chromatographed on silica(60-200 mesh); elution with ethyl acetate/hexane (25/75), yielded methyl2alpha,3alpha-epoxy-5alpha-hydroxy-5beta-trimethylsilyethynylcyclohexane-carboxylate(273 mg, 86%) as white crystals. The spectroscopic data showed that theproduct was identical with that obtained using t-butyl hydroperoxide(Example 4).

Example 27 Methyl5beta-ethynyl-3alpha,5alpha-dihydroxy-1-cyclohexene-1-carboxylate.

Sodium methoxide (410 mg, 76 mmol) was added to a mixture ofmethyl-5alpha-hydroxy-5betatrimethylsilylethynyl-2alpha,3alpha-epoxycyclohexane-1alpha-carboxylate(2.01 g, 75 mmol) and methanol (20 mL) and stirred at room temperatureovernight. The mixture was neutralized to pH 7 and extracted with ethylacetate (5×50 mL) The combined extracts were washed with aqueoussaturated NaCl solution (50 mL), dried over Na,SO₄, passed through ashort plug of silica and eluted with ethyl acetate (100 mL). Evaporationof the solvent gavemethy15beta-ethynyl-3alpha,5alpha-dihydoxy-1-cyclohexene-1-carboxylate(1.4 g, 96%) as white crystals:mp:111-112 degrees Celsius; ¹ H NMR (500MHz, CDCl₃, ppm): 7.03 (m, 1H, ═CH), 4.35 (m, W_(1/2) =11 Hz, J_(H2-H3)=3.23 Hz, C₃ --H), 3.80 (s, 3H, OCH₃), 2.82 (dd, 1H), 2.67 (bs, 2H, OH),2.60 (dt, 1H), 2.55 (s, 1H, ═CH), 2.30 (dq, 1H,);

13C NMR (125 mHz, CDCl₃ ppm): 167.12, 138.01, 127.51, 88.96, 72.41,66.29, 64.51, 51.99, 41.58, 38.35; FT-IR (KBr, cm⁻¹): 3406 (b, OH), 3290(═CH, 2110 (C═C), 1716 (C═O), 1652.

Example 28Methyl-3beta-ethynyl-3alpha,5alpha-dihydroxy-6alpha-nitromethyl-cyclohexane-1beta-carboxylate.

1,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU, 0.95 g, 6.26 mmol) was addedto a mixture of methyl3alpha,5alpha-dilhydroxy-5beta-ethynyl-1-cyclohexene carboxylate (1.28g, 6.53 mmol) in CH₃ NO₂ (5 mL) and DMSO (3 mL) at 0 degrees Celsius.This was stirred at room temperature for 12 hours, when TLC showed thatall the starting diol had disappeared. HCL (50 mL. 0.1N) was added at 0degrees Celsius. The mixture was extracted with ethyl acetate (4×30 mL).The combined extracts were washed with saturated aqueous NaCl solution(2×30 mL). Evaporation of the solvents yielded light yellow liquid (1.94g). The crude product was chromatographed (60-200 mesh flash silica),eluting with 50/50 ethyl acetate and hexane to give two products. Thefirst product was obtained as colorless crystals of methyl3beta-ethynyl-3alpha,5alpha-dihydroxy-6alpha-nitromethyl-cyclohexane-1beta-carboxylate (0.6 g39.2%), m.p. 99-100 degrees Celsius (recrystallized from ethyl acetateand hexane); FT-IR (KBr, cm⁻¹): 3480 (OH), 3280 (═CH), 1720 (C═O), 1542(NO₂); ¹ H NMR (500 MHz, CDCl₃) delta: 4.62 (dd, J_(gem) =12.3 HzJ_(HCNO2-H6e) =8.06 Hz, 1H, CHNO₂), 4.49 (dd, J_(gem) =12.3 Hz,J_(HCNO2-H6e) =6.54 Hz, 1H, CHNO₂). 4.12. (q.J_(H5e-H4e) =4.43 Hz,J_(H5e-H4a) =4.43 Hz, J_(H5e-H6e) =4.83 Hz, 1H, C₅ H_(e)), 3.71 (s, 3H,OCH₃). 3.50 (b, 2H, 2OH), 3.32 (m, J_(H1a-H2a) =8.87 Hz, J_(H1a-H2e)=4.84 Hz, J_(H1a-H6e) =4.43 Hz, 1H, OOCCH), 2.89 (m, 1H, C_(6H) e), 2.54(s, 1H, ═CH), 2.08 (m, 2H, C₄ H_(e) C_(2HeJH4e-H5e) =4.43 Hz,JH2e-H1a=4.84 Hz), 2.07 (m, 2H, C4Ha, C2Ha, JH4a-H5e=4.43 Hz,J_(H2a-H1a) =8.86 Hz); ¹³ C NMR (75 MHz, CDCl₃) delta: 173.16, 85.5,74.34, 73.12, 67.42, 66.67, 52.11, 41.31, 41.22, 37.54, 36.11. The cisisomer has also isolated.

Example 29Methyl-3beta-ethynyl-3alpha,5alpha-dihydroxy-6alpha-nitromethyl-cyclohexane-1beta-carboxylate

1.8-diazabicyclo-[5,4,0]-undec-7ene(DBU), 54, ul, 0.33 mmol) was addedto a mixture of methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-1-cyclohexene carboxylate (65 mg,0.33 mmol) in CH₃ NO₂ (2 mL) and (CH₃)₃ NO (161 mg, 1.99 mmol) at 0degrees Celsius. This was stirred at room temperature for 4 hours, whenTLC showed that all the starting diol had disappeared. HCL (5 mL, 0.1N)was added 0 degrees Celsius. The mixture was extracted with ethylacetate (4×5 mL). The combined extracts were washed with saturatedaqueous NaCl solution (2×10 mL). Evaporation of the solvents yieldedlight yellow liquid (90 mg). The crude product was chromatographed(60-200 mesh flash silica), eluting with 50/50 ethyl acetate and hexaneto give two products. The first product was obtained as colorlesscrystals of methyl3beta-ethynyl-3alpha,5alpha-dihydroxy-6alpha-nitromethyl-cyclohexane-1beta-carboxylate(33 mg, 39%), Mp. 99-100 degrees Celsius (recrystallized from ethylacetate and hexane). The spectroscopic data on this compound isidentical with that of Example 28.

Example 30 Methyl3beta-ethynyl-3alpha,5alpha-(di-O-Isopropylidenyl-6alpha-nitromethyl-cyclohexane-1alpha-carboxylate.

To a solution of methyl 3beta-ethynyl-3alpha,5alpha-dihydroxy-6alpha-nitromethyl cyclohexane-1beta-carboxylate (1.5g, 5.84 mmol) in benzene (50 ml), pyridium tosylate (PPTS, 5 mg)2-methyoxypropene (5.9 mmol) was added and the mixture was kept at roomtemperature until TLC shown that all starting material was gone (about15 min). Then additional 2-methoxypropene (0.5 ml, 4.9 mmol) was and themixture was refluxed for 5 minutes. The reaction solution was cooled toroom temperature, and saturated aqueous NaHCO₃ solution (15 mL) wasadded. The aqueous layer was extracted with ethyl acetate (2×20 mL), thecombined organic layers were washed with saturated aqueous NaCl solution(2×20 mL) and dried over (Na₂ SO_(b) 4). The solvent was removed invacuo. The light yellow residue was passed through a short plug ofsilica and eluted with ethyl acetate and hexane (25:75, 200 ml) toafford methyl5beta-ethynyl-3alpha,5alpha-(di-O-isopropylidenyl)-6alpha-nitromethyl-cyclohexane-1beta-carboxylateas a colorless oil.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

Although preferred embodiments of the invention have been described withsome particularity, many modifications and variations in the preferredembodiment are possible without deviating from the invention. Is ittherefore to be understood that, within the scope of the appendedclaims, the invention may be practiced other than as specificallydescribed.

What is claimed is:
 1. A process for the production of daunomycinone, orits 6-desoxy-6-nitro, 6-desoxy-6-amino, 6 desoxy-6-cyano, 6-desoxy, or6-halo-6-desoxy analogues comprising the steps of:condensing theacetonide of methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1alphacarboxylatewith 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene in the presence of1,8-diazabicyclo [5.4.0]undec-7-ene in the presence of a hydrogen bondacceptor to produce 3-[2beta-carbomethoxy-4beta-ethynyl-4alpha,6alpha-(di-O-isopropylidenyl)cyclohexan-1-yl]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene;and cyclizing said 1-oxotetrahydronaphthalene to produce7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-6-nitro-4,5,5-trimethoxy-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenone; the step of cyclizingsaid 1-oxotetrahydronaphthalene including the steps of converting saiddecahydro-11-naphthacenone to7alpha,9alpha-(di-O-isopropylidenyl)-4,5-dimethoxy-9beta-ethynyl-12-hydroxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone, oxidizing said octahydro-11-naphthacenoneto7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedione,hydrolysing said 5,12-naphthacenedione to 6-desoxy-6-nitrodaunomycinone,reducing said nitronaphthacenedione to6-amino-7alpha,9alpha-(di-O-isoproylidenyl)-9beta-ethynyl-11-hydroxy-4-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione,and converting said aminonaphthacenedione by way of the 6-diazoniumderivatives to daunomycinone, 6-desoxydaunomycinone, the6-desoxy-6-halodaunomycinones, or said analogues.
 2. The process ofclaim 1 wherein 1-oxotetrahydronaphthalene is cyclized with an alkalimetal alkoxide of 1-6 carbon atoms.
 3. The process of claim 1 whereinsaid decahydro-11-naphthacenone is converted to7alpha,9alpha-(di-O-isopropylidenyl)-4,5-dimethoxy-9beta-ethynyl-12-hydroxy-6-nitro6,6a,7,8,9,10,10a, 11-octahydro-11-napthacenone under acidic conditions.4. The process of claim 1 wherein said octahydro-11-naphthacenone isoxidized to 7alpha,alpha-(di-O-isopropylidenyl)-9beta-ethynyl-11-hydroxy-4-methoxy-6-nitro-97,8,9,10-tetrahydro-5,12-naphthacenedione with a reagent selected from agroup consisting of cerium ammonium nitrate, thallium trinitrate, andiodobenzenediacetate, using with each oxidant a catalytic quantity of2,3-dichloro-5,6-dicyanobenzoquinone.
 5. A process for the production ofderivatives of daunomycinone, comprising the steps of:condensing theacetonide of methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1alpha-carboxylatewith 1,4-dihydro-4,4,5-trimethoxy-1-oxonaphthalene in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene in an aprotic solvent to produce3-[2beta-carbomethoxy-4beta-ethynyl-4alpha,6alpha-(di-O-isopropylidenyl)cyclohexan-1-yl]-nitromethyl-4,4,5-trimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene;and cyclizing said 1-oxotetrahydronaphthalene to produce7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-12-hydroxy-6-nitro-4,5,5-trimethoxy-5,5a,6,6a,7,8,9,10,10a,11-decahydro-11-naphthacenonecharacterized by converting said decahydro-11-naphthacenone to7alpha,9alpha-(di-O-isopropylidenyl)-4,5-dimethoxy-9beta-ethynyl-12-hydroxy-6-nitro-6,6a,7,8,9,10,10a,11-octahydro-11-naphthacenone;converting said octahydro-11-naphthacenone to7alpha,9alpha-(di-O-isopropylidenyl-11-imino-6-nitro-6,6a,7,8,9,10,10a,11-octahydronaphthacenewith methanol and ammonia; oxidizing the7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-11-imino-6-nitro-6,6a,7,8,9,10,10a,11-octahydronaphthaceneto11-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedionewith cerium ammonium nitrate and a catalytic amount ofdichlorodicyanobenzoquinone or O₂ /DMF; hydrolyzing hydrating the11-amino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-6-nitro-7,8,9,10-tetrahydro-5,12-naphthacenedioneto 11-amino-6,11-didesoxy-6-nitrodaunomycinone with acid and mercuricoxide; converting aminonitrodaunomycinone by the diazonium salt to6,11-didesoxy-6-nitrodaunomycinone; reducing said11-amino-6-nitronaphthacenedione with stannous chloride in methanol to6,11-diamino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione;hydrolyzing and hydrating said diamino naphthacenedione to 6,11-diamino6,11-didesoxy daunomycinone.
 6. A process according to claim 5 whereinthe6,11-diamino-7alpha,9alpha-(di-O-isopropylidenyl)-9beta-ethynyl-4-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedioneis converted to 6,11-diamino-6,11-didesoxydaunomycinone using HgO underacidic conditions.
 7. A process according to claim 6 whereinthe11-amino-6,11-didesoxy-6-nitrodaunomycinone is converted into an 11-haloderivative through the 11-diazonium-6-nitrodaunomycinone; the 11-halo isconverted to a selected one of the groups consisting of6-hydroxy-11-fluoro, 11-chloro, 11-bromo and 11-iodo daunomycinones byway of the 6-diazonium compound; and the 6-diazonium compounds of the11-halo compounds are converted to the corresponding one of the11-halo-6-fluoro, 6-chloro, 6-bromo and 6-iodo daunomycinones.
 8. Aprocess of synthesizing methylcis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylateand methyl cis 3,5-dihydroxy-5-ethynyl cyclohex-1-ene-1 carboxylate fromm-anisic acid characterized by Birch reduction with lithium in ammoniato produce 5-oxocyclohex-2-ene-1-carboxylic acid, methylation of saidcyclohex-2-ene-1-carboxylic acid to methyl5-oxo-cyclohex-2-ene-1-carboxylate with diazomethane,trimethylsilylethynylation of said cyclohex-2-ene-1-carboxylate withcerium dichloride trimethylsilylacetylene to produce methylcis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate, andconversion to an epoxide and opening of the resulting epoxide ring togive said cyclohex-1-ene-1-carboxylates.
 9. The process of claim 8characterized in that the reaction mixture is kept cold duringesterification with diazomethane and the ethanol that is present in theesterification reaction mixture is removed by azeotropic distillationwith benzene, methyl ester is treated with cerium dichloridetrimethylsilylacetylene at a low temperature to prevent formation of alactone, the epoxide is formed by oxidation with t-butyl hydroperoxidein the presence of molybdenum hexacarbonyl catalyst and molecular sievesor by oxidation with cumyl hydroperoxide catalysed by titaniumtetraisopropoxide and isolating the thus-produced epoxide and theepoxide ring is opened with 1,8-diazabicyclo[5.4.0]-undec-7-ene or1,5-diazabicyclo[4.3.0]non-5-ene or sodium methoxide in methanol; thelatter conditions also remove the trimethysilyl group to give methylcis3,-5-dihydroxy-5-ethynylcyclohex-1-ene-1-carboxylate. 10.3,5-acetonide of methyl3alpha,5alpha-dihydroxy-5beta-(tri-methylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate.11. A process for producing methyl3alpha,5alpha-dihydroxy-5beta-ethynyl-2alpha-nitromethylcyclohexane-1beta-carboxylatecomprising the steps of reacting methylcis-3,5-dihydroxy-5-beta-ethynylcyclohex-1-ene-1-carboxylate withnitromethane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or1,5-diazabicyclo[4.3.0]non-5-ene or sodium hydride or potassium hydridein an aprotic solvent which can form hydrogen bonds with hydroxylgroups.
 12. A process for preparing methyl3-alpha,5-alpha-dihydroxy-5-beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1-beta-carboxylatecharacterized by reacting methylcis-(2,3alpha-epoxy-5alpha-hydroxy-5beta-(trimethylsilylethynyl)cyclohexane-1alpha-carboxylatewith nitromethane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-enein the presence of a substance that can form hydrogen bonds withhydroxyl groups.
 13. A compound of the general formula: ##STR9## whereinR₁ is one of: CH₃ or CH₂ OH; R₂ is one of daunosamine, or H;R₃ is one ofOH, NO₂, NH₂, F, Cl, Br, I, CN and H or groups derived from these; R₄ isone of NO₂, NH₂, F, Cl, Br, I and CN or groups derived or substitutedfor these; and R₅ is OCH₃, OH or H; R₅, R₆, R₇ are all H or R₅ and R₆are H and R₇ and R₈ are alkyl or halo; or R₅ and R₆ are alkyl or haloand R₇ and R₈ are H.
 14. A compound according to claim 13 wherein thecompound is 11-amino-6,11-didesoxy-6-nitrodaunomycinone.
 15. A compoundaccording to claim 13 wherein the compound is6,11-diamino-6,11-didesoxydaunomycinone.
 16. A compound according toclaim 13 wherein the compound is a 11-halo derivative.
 17. A compoundaccording to claim 13 wherein the compound is a 11-cyano derivatives.18. A compound according to claim 13 wherein the compound is a compoundselected from the group consisting of the 11-halo and11-cyano-6-nitrodaunomycinones.
 19. A compound according to claim 10wherein the compound is a 11-flourine derivative.
 20. A compoundaccording to claim 13 wherein the compound is selected from the group ofcompounds consisting of 6,11-difluro, 6,11-dichloro, 6,11-dibromo,6,11-diiodo and 6,11-dicyano daunomycinones.
 21. Methyl3alpha,5alpha-dihydroxy-5beta-(trimethylsilylethynyl)-2alpha-nitromethylcyclohexane-1beta-carboxylate.22. A process according to claim 6 wherein one of:the11-amino-6,11-didesoxy-6-nitrodaunomycinone is converted into an11-cyano derivative through the 11-diazonium-6-nitrodaunomycinone; the6-diazonium compounds of the cyano compounds are converted to 6-cyanodaunomycinone.
 23. A process according to claim 7 wherein6,11-diamino-6,11-didesoxydaunomycinone is converted to a selectedcompound from the group consisting of 6,11-difluro, 6,11-dichloro,6,11-dibromo, 6,11-diiodo and 6,11-dicyano daunomycinones.